The Dipeptidyl Peptidase-4 Inhibitor Saxagliptin As a Candidate Treatment for Disorders of Consciousness: A Deep Learning and Retrospective Clinical Analysis

Background: Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes.

Methods: To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury.

Results: Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage.

Conclusions: Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.